HIV protease is an essential enzyme for the replication of human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS). Within the last decade, the enzyme has become recognized as a virus-specific therapeutic target. As a result, much attention has been focused on the development of HIV protease inhibitors for the treatment of AIDS. For a recent review on the state of HIV protease inhibitors, see S. Thaisrivongs, Annual Reports In Medicinal Chemistry, 1994, 29, 133.
As noted in the latter review, potent HIV protease inhibitors have been realized by the placement of a hydroxyethylamine isostere (also known as a hydroxyethylamine transition state analog) in a peptide having the p17/p24 substrate cleavage site sequence.
Noteworthy reports describing HIV protease inhibitors with hydroxyethytamine isosteres incorporated therein include N. A. Roberts et al., Science, 1990, 248, 358; D. P. Getman et al., J. Med. Chem., 1993, 36, 288; and P. C. Anderson et al., European patent application, publication no. 560 268, Sep. 15, 1993.
As exemplified in the last three references, an often-used intermediate for the elaboration of the hydroxyethylamine isostere-containing inhibitors is an aminoepoxide intermediate represented by the following general formula A: ##STR3## wherein X is an N-protective group, Y is hydrogen or an N-protective group, and R is a typical amino acid side chain; for example, phenylmethyl derived from phenylalanine, or protected amino acid side chain, for example, {4-(phenylmethoxy)phenyl}methyl derived from tyrosine.
Note that the above general formula for the aminoepoxide intermediate contains two asymmetric carbon atoms.
Preferred enantiomerically pure amino epoxide intermediates for the preparation of the hydroxyethylamine isostere containing HIV protease inhibitors are those in which the carbon atom bearing the nitrogen atom and the carbon atom bearing the oxygen atom both have the (S) configuration.
Hence, in view of high profile of the intermediates, a process for the preparation of the enantiomerically pure (S,S)-aminoepoxide intermediates, which meets the criteria of being efficient, safe and amenable to scale-up, is most desirable.
Paradoxically, the reported preparations of the desired enantiomerically pure aminoepoxide intermediates, or chemical equivalents thereof, do not meet the aforementioned three criterea.
More explicitly, B. E. Evans et al., J. Org. Chem., 1985, 50, 4615 reports the synthesis of enantiomerically pure aminoepoxide intermediates by reacting the corresponding Boc-.alpha.-amino aldehydes with dimethylsulfonium methylide and separating the resulting mixture of diastereoisomeric epoxides. This method suffers from the lack of stereoselectivity, the use of a hazardous combination of sodium hydride and dimethylsulfoxide, as well as the use of chromatography to separate diastereoisomers, a step not easily amenable to scale-up.
M. T. Reetz and J. Binder, Tetrahedron Letters, 1989, 30, 5425 describe a similar process involving the reaction of N,N-(doubly protected)-.alpha.-aminoaldehydes with dimethylsulfonium methylide. Although the N,N-(doubly protected)-.alpha.-aminoaldehyde lends itself to a more stereoselective conversion, the process suffers from the aforementioned disadvantages of safety and the need to separate the mixture of diastereoisomeric products by chromatography. The authors note on page 5428 (reference 8) that the separation of the diastereoisomeric products (aminoepoxide) is difficult and suggest the separation of later oxirane-ring opened products as a more practical method to diastereomerically pure products.
Recently, A. Albeck and R. Persky, Tetrahedron, 1994, 50, 6333 described a multistep process for preparing aminoepoxide intermediates. The process utilizes an .alpha.-(chloromethyl)-.gamma.-N-(benzyloxycarbonyl) aminoketone precursor which is synthesized in turn by a step involving diazomethane. The use of diazomethane, a hazardous reagent, limits this process to small scale preparations.
Again recently, J. S. Ng et al., PCT patent application WO 93/23388, published Nov. 25, 1993 reported a process for preparing the aminoepoxide intermediate by reacting N,N-doubly protected-.gamma.-amino aldehydes with a halomethyllithium reagent generated in situ from chloroiodomethane and butyllithium to give the aminoepoxide intermediate as a mixture of diastereoisomers. Although the isolation of two diastereomerically pure aminoepoxide intermediates by chromatography is described, like Reetz and Binder, supra, Ng et al. recommend that the diastereoisomeric mixture of the aminoepoxide intermediate be used directly for further elaboration of the ultimate end product, saving the separation of diastereoisomers for a later stage.
The Ng et al. process has the disadvantages of (1) requiring chromatographic separation of the diasteroisomeric mixture to obtain the desired isomerically pure intermediate; (2) using pyrophoric butyllithium; and (3) forming an environmentally undesirable side product, namely butyliodide.
Similarly to the Ng et al. patent application, J. Barluenga et al., J. Chem. Soc., Chem. Commun., 1994, 969, disclose the preparation of a N,N-doubly protected aminoepoxide intermediate by reacting N,N-dibenzylalaninal with chloromethyllithium generated in situ from chloroiodomethane and methyllithium. This preparation has disadvantages similar to those as noted in the preceding paragraph.
The present process, on the other hand, fulfills the need for a safe, efficient process that can be worked on a large scale. The process has the features of simplicity and expediency, and it avoids the use of hazardous chemicals. The process efficiently and economically produces the desired intermediate, or a chemical equivalent thereof, with an enantiomeric and diastereomeric purity of 95% or greater.